The aging nonhuman primate manifests many changes in the brain reminiscent of the human condition. The current study examined the anatomical correlates to reports of cognitive decline ascribed to decreased dopamine in the prefrontal cortex (PFC). Initially, midbrains from young (<4 yrs.), middle-aged (10-15 yrs.) and old (20-30 yrs) male rhesus macaques were probed for mRNA levels of tyrosine hydroxylase (TH) by in situ hybridization, using a monkey-specific cRNA probe. TH is the rate-limiting enzyme in the catecholaminergic synthesis pathway. Hybridization signal in the substantia nigra and ventral tegmental area dropped significantly by middle-age and continued to decrease with age. Thus, decreased expression of TH mRNA from projecting midbrain dopaminergic neurons may account for the reported age-related decline in PFC DA levels. Additionally, PFCs from the same animals showed increased astrocytic gliosis and amyloid plaque deposition as a function of age, although plaques were seen only in the old group and were variable in location and relative density. Finally, PFC mRNA levels of the NMDA excitatory amino acid receptor subunit, NR1, were significantly decreased in only the old group of animals. In order to detect progressive age-related changes in vivo, we have started to use Magnetic Resonance Imaging on the animals. Volumetric changes with age will be examined in major gray and white matter areas as a predictor of cognitive deficits with senescence.